Molecular, Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Molecular, Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Biochim Biophys Acta Mol Cell Res. 2018 Sep;1865(9):1356-1367. doi: 10.1016/j.bbamcr.2018.06.014. Epub 2018 Jun 30.
Lysosomes are a major organelle for degrading macromolecules. When deprived of nutrients, cells activate the autophagy and lysosome biogenesis pathways to recycle cytoplasmic materials and to increase lysosomal degradation capacity for survival, respectively. We have identified a condition in which cells accumulated enlarged lysosomes upon starvation and lysosome inhibition. Selective autophagy and inhibition of the mechanistic target of rapamycin (mTOR) in combination with lysosome inhibition were not able to induce this phenomenon. Conversely, knocking out autophagy genes, ATG5 or ATG7, had no effects on the enlarged lysosome formation. This suggests that the enlarged lysosome formation is an autophagy independent process. Remarkably, adding glutamine to the treatment can prevent formation of the enlarged lysosomes and dissipate the pre-existing ones. Furthermore, the nucleus/cytoplasm translocation of the transcription factor EB (TFEB), but not mTOR activity, correlates with the formation/dissipation of enlarged lysosomes. Knockdown of TFEB, however, suggests that TFEB-mediated lysosome biogenesis is not directly involved in the process. These results indicate that there is a novel mechanism by which lysosome homeostasis can be regulated under certain stress conditions.
溶酶体是降解大分子的主要细胞器。当细胞缺乏营养时，它们会分别通过自噬和溶酶体生物发生途径来回收细胞质物质并增加溶酶体的降解能力，以维持生存。我们发现了一种在饥饿和溶酶体抑制时细胞积累大溶酶体的情况。选择性自噬和雷帕霉素（mTOR）的机械靶点抑制剂与溶酶体抑制剂的联合抑制均不能诱导这种现象。相反，敲除自噬基因 ATG5 或 ATG7 对大溶酶体的形成没有影响。这表明大溶酶体的形成是一个独立于自噬的过程。值得注意的是，向处理中添加谷氨酰胺可以防止大溶酶体的形成并消散已有的大溶酶体。此外，转录因子 EB（TFEB）的核/细胞质易位与大溶酶体的形成/消散相关，而不是 mTOR 活性。TFEB 的敲低表明 TFEB 介导的溶酶体生物发生不是直接参与该过程。这些结果表明，在某些应激条件下，溶酶体稳态可以通过一种新的机制来调节。
